Leishmaniasis is a chronic protozoal disease of man. Our goal is to define mechanisms responsible for this chronicity using experimental murine infections. We describe several factors that influence cutaneous leishmaniasis, including: (1) resistance to killing of some leishmanial strains, (2) impaired ability of macrophages to be activated to kill Leishmania at cutaneous temperatures, and (3) inability of specifically elicited macrophages from infected BALB/c mice to kill Leishmania. We found that infected BALB/c mice also develop a peritoneal eosinophilia, and the relationship between this eosinophilia and BALB/c susceptibility is being investigated. In additionm Mu-suppression from birth altered leishmanial infections in C3H/HeN mice, converting a self-healing infection to a chronic one. Results from cell transfer experiments suggest that B cells and/or antibodies may be required for the development of a T cell necessary for healing leishmanial infections. Finally, we used an experimental vaccine to study how the chronicity of leishmanial infections can be circumvented. Immunization of C3H/HeN mice was achieved by intradermal injection of irradiated promastigotes, while protection in BALB/c mice was only obtained by the intravenous route. At present, the effector mechanism of this vaccine is not known. However, we found that macrophages from protected mice do not develop the resistance to activation described above. With regard to the immunogens involved, both particulate and soluble fractions were protective, but only if they were isolated with the appropriate protease inhibitors. Moreover, preliminary experiements suggest that while logarithmic growth phase promastigotes and amastigotes are protective, stationary growth phase promastigotes are not protective. Work is currently focusted on defining the protective immunogenes.